The human major histocompatibility complex (MHC) contains genes that encode products that are fundamental regulatory elements of the immune response. Alleles and combinations of alleles of each of the loci were examined to determine their contribution to a number of diseases. In 241 individuals infected with HIV-1, HLA class I alleles or combinations of class I alleles with individual sites of variation of the transporter genes for antigen processing (TAP1, TAP2) were found to be associated with a relatively prolonged interval from infection to AIDS diagnosis. Other HLA class I alleles were found to be associated with rapid disease progression only when associated with two variants of the TAP2 genes. In addition, four different HLA class II haplotypes, when present with a variant of the TAP1 gene, were found in individuals with rapid progression. To further elucidate the mechanism that accounts for rapid and slow disease progression, the frequencies of motifs that anchor peptides to individual class I alleles were determined in viral sequences. Higher frequencies of these peptides were found in alleles associated with a prolonged disease-free interval and significantly lower frequencies in alleles associated with rapid disease progression. Alleles of some genes in the MHC are unique in their frequency of association, and thus represent a high degree of linkage disequilibrium. We have identified a 15-kilobase region in the chromosome that contains the TAP genes. Four microsatellite markers in this region as well as other polymorphic sites in the class I, class II and class III regions were used to identify recombination frequencies in 59 Centre d'Etude du Polymorphisme Humaine family pedigrees. The absence of HLA class I and class II expression in malignant melanoma is thought to be a mechanism whereby the tumor escapes immune surveillance. Expression of TAP gene products are required for stable class I expression of the cell surface. Freshly explanted melanoma tumor cells from eleven patients were examined for the presence of surface HLA class I of which seven were deficient. Five of these were found to have absent messages for one or both TAP genes.